Synthesis of Morphine

C17H19NO3

Principal investigator	Gilbert Stork
Publication year	2009
Synthesis type	Formal
Number of steps	22 (linear)
References	J. Am. Chem. Soc. 2009, 131, 11402.

Part 1 of 1

TsOH, HO(CH2)3OH

Dean-Stark

PhMe

Reflux, 85%

Et3N, Methyl propynoate

THF

-20 to 0 °C, 3.5 h, 89%

See the Michael Addition

NaOAc, Pd(OAc)2, Ph3P, n-Bu4N+ Cl-

DMF, H2O

125 °C, 4 h, 84%

See the Mizoroki-Heck Reaction

HCl

H2O, THF

0 °C, 90 min, 80%

TMS2NK, Ph3P+CH2OMe Cl-

CH2Cl2, THF

-30 °C to RT, 15.5 h, 95%

See the Wittig Reaction

HCl

H2O, THF

RT, 2.5 h, 86%

AgOTf , Cp2ZrHCl
Imidazole , TESCl

CH2Cl2

-78 °C to RT, 19.5 h, 95%

Et3N

																	Decalin															

								235-240 °C, 								24 h, 								55%
							
								See the Diels-Alder Reaction
							
								"The yield was 70 % brsm. Also isolated was the C2-epimer (14 % yield)."

LiBHEt3

CH2Cl2

0 °C, 90 min, 86%

"The yield was 90 % brsm."

Dess-Martin Periodinane

CH2Cl2

0 °C to RT, 3.5 h

See the Dess-Martin Oxidation

Ph3P+CH2OMe Cl-, TMS2NK

CH2Cl2, THF

-50 °C to RT, 15 h, 74% (2 steps)

See the Wittig Reaction

n-Bu4N+ F-

THF

-50 °C to RT, 2 h, 88%

Dess-Martin Periodinane

CH2Cl2

0 °C, 4.5 h, 90%

See the Dess-Martin Oxidation

Li(s-Bu)3BH

THF

-20 °C to RT, 6 h, 53%

"The yield was 70 % brsm."

Et3N, MsCl

CH2Cl2

0 °C, 6 h, 74%

"The yield was 90 % brsm."

HCl

H2O, THF

0 °C, 5 h, 86%

"The yield was 98 % brsm."

Et3N, NaBH4, Ti(Oi-Pr)4, MeNH2.HCl

MeOH

0 °C to RT, 4 h, 93%

K2CO3

PhH

75 °C, 24 h, 73%

NaHCO3, ClCO2Me

CHCl3

Reflux, 17 h, 91%

SeO2, t-BuOOH

H2O

Reflux, 15 h, 72%

"The yield was 89 % brsm."

LiAlH4

Et2O

-30 °C to Reflux, 3.5 h, 82%

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Remaining...

91% (1 step)

"See : J. Med. Chem. 1977, 20, 164."